1. Field of the Invention
The present invention relates to aminoalkyl substituted 5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole and 5,6,7,8-tetrahydro-9H-pyrimidino[4,5-b]indole derivatives, pharmaceutical compositions containing such compounds and their use in treating psychiatric disorders, neurological diseases, immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress.
2. Description of the Related Art
Corticotropin releasing factor (herein referred to as CRF), a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin (POMC) derived peptide secretion from the anterior pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain [W. Vale et al., Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There is also evidence that CRF plays a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors [J. E. Blalock, Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci. 41:527 (1987)].
Clinical data provide evidence that CRF has a role in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and feeding disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer""s disease, Parkinson""s disease, Huntington""s disease, progressive supranuclear palsy and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF neurons in the central nervous system [for review see E. B. De Souza, Hosp. Practice 23:59 (1988)].
In affective disorder, or major depression, the concentration of CRF is significantly increased in the cerebral spinal fluid (CSF) of drug-free individuals [C. B. Nemeroff et al., Science 226:1342 (1984); C. M. Banki et al., Am. J. Psychiatry 144:873 (1987); R. D. France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al., Biol Psychiatry 25:355 (1989). Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF [C. B. Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. In addition, there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v. administered) observed in depressed patients [P. W. Gold et al., Am J. Psychiatry 141:619 (1984); F. Holsboer et al., Psychoneuroendocrinology 9:147(1984); P. W. Gold et al., New Eng. J. Med. 314:1129 (1986)]. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms seen in human depression [R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the numbers of CRF receptors in brain [Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)].
There has also been a role postulated for CRF in the etiology of anxiety-related disorders. CRF produces anxiogenic effects in animals and interactions between benzodiazepine/non-benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models [D. R. Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J. Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the putative CRF receptor antagonist xcex1-helical ovine CRF (9-41) in a variety of behavioral paradigms demonstrate that the antagonist produces xe2x80x9canxiolytic-likexe2x80x9d effects that are qualitatively similar to the benzodiazepines [C. W Berridge and A. J. Dunn Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71 (1990)]. Neurochemical, endocrine and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics providing further evidence for the involvement of CRF in these disorders. Chlordiazepoxide attenuates the xe2x80x9canxiogenicxe2x80x9d effects of CRF in both the conflict test [K. T. Britton et al., Psychopharmacology 86:170 (1985); K. T. Britton et al., Psychopharmacology 94:306 (1988)] and in the acoustic startle test [N. R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. The benzodiazepine receptor antagonist Ro l5-1788, which was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner while the benzodiazepine inverse agonist FG 7142 enhanced the actions of CRF [K. T. Britton et al., Psychopharmacology 94:306 (1988)].
It has been further postulated that CRF has a role in immunological, cardiovascular or heart-related diseases such as hypertension, tachycardia and congestive heart failure, stroke and osteoporosis. CRF has also been implicated in premature birth, psychosocial dwarfism, stress-induced fever, ulcer, diarrhea, post-operative ileus and colonic hypersensitivity associated with psychopathological disturbance and stress. The mechanisms and sites of action through which the standard anxiolytics and antidepressants produce their therapeutic effects remain to be elucidated. It has been hypothesized however, that they are involved in the suppression of the CRF hypersecretion that is observed in these disorders. Of particular interest is that preliminary studies examining the effects of a CRF receptor antagonist (xcex1-helical CRF9-41) in a variety of behavioral paradigms have demonstrated that the CRF antagonist produces xe2x80x9canxiolytic-likexe2x80x9d effects qualitatively similar to the benzodiazepines [for review see G. F. Koob and K. T. Britton, In: Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E. B. De Souza and C B Nemeroff eds., CRC Press p221 (1990)].
In one aspect, the present invention provides novel compounds which bind to corticotropin releasing factor receptors, thereby altering the anxiogenic effects of CRF secretion. The compounds of the present invention are useful for the treatment of psychiatric disorders and neurological diseases, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress in mammals. In another aspect, the present invention provides novel compounds of Formula I (described below) which are useful as antagonists of corticotropin releasing factor. The compounds of the present invention exhibit activity as corticotropin releasing factor antagonists and suppress CRF hypersecretion. The present invention also provides pharmaceutical compositions containing such compounds of Formula I, and methods of using such compounds for the suppression of CRF hypersecretion, and/or for the treatment of anxiogenic disorders.
According to yet another aspect, the present invention provides novel compounds, pharmaceutical compositions and methods for the treatment of affective disorder, anxiety, depression, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer""s disease, gastrointestinal disease, anorexia nervosa or other feeding disorder, drug or alcohol withdrawal symptoms, drug addiction, inflammatory disorder, fertility problems, disorders, the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, or a disorder selected from inflammatory disorders such as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and allergies; generalized anxiety disorder; panic, phobias, obsessive-compulsive disorder; post-traumatic stress disorder; sleep disorders induced by stress; pain perception such as fibromyalgia; mood disorders such as depression, including major depression, single episode depression, recurrent depression, child abuse induced depression, and postpartum depression; dysthemia; bipolar disorders; cyclothymia; fatigue syndrome; stress-induced headache; cancer, human immunodeficiency virus (HIV) infections; neurodegenerative diseases such as Alzbeimer""s disease, Parkinson""s disease and Huntington""s disease; gastrointestinal diseases such as ulcers, irritable bowel syndrome, Crohn""s disease, spastic colon, diarrhea, and post operative ilius and colonic hypersensitivity associated by psychopathological disturbances or stress; eating disorders such as anorexia and bulimia nervosa; hemorrhagic stress; stress-induced psychotic episodes; euthyroid sick syndrome; syndrome of inappropriate antidiarrhetic hormone (ADR); obesity; infertility; head traumas; spinal cord trauma; ischemic neuronal damage (e.g., cerebral ischemia such as cerebral hippocampal ischemia); excitotoxic neuronal damage; epilepsy; cardiovascular and heart related disorders including hypertension, tachycardia and congestive heart failure; stroke; immune dysfunctions including stress induced immune dysfunctions (e.q., stress induced fevers in humans and the following animal diseases: porcine stress syndrome, bovine shipping fever, equine paroxysmal fibrillation, and dysfunctions induced by confinement in chickens, sheering stress in sheep or human-animal interaction related stress in dogs); muscular spasms; urinary incontinence; senile dementia of the Alzheimer""s type; multiinfarct dementia; amyotrophic lateral sclerosis; chemical dependencies and addictions (e.g., dependencies on alcohol, cocaine, heroin, benzodiazepines, or other drugs); drug and alcohol withdrawal symptoms; osteoporosis; psychosocial dwarfism and hypoglycemia in mammals.
Such methods involve administration to a mammal of a therapeutically effective amount of a compound of Formula I.
In yet another aspect of the invention, the compounds provided the invention (and especially radio-labeled compounds of this invention) are also useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the CRF receptor.
The compounds encompassed by the instant invention and represented by general Formula I: 
wherein:
Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, carboxamido, C1-C6 alkyl, C1-C6 alkoxy, with the proviso that at least one of the positions ortho or para to the point of attachment of Ar to the tricyclic ring system is substituted;
R1 is hydrogen, halogen, trifluoromethyl, C1-C6 alkyl, or (C1-C6 alkyl)-G1xe2x80x94R2 where G1 is oxygen or sulfur and R2 is hydrogen or C1-C6 alkyl;
W is N or Cxe2x80x94R3 where R3 is hydrogen or C1-C6 alkyl;
m is 0, 1, or 2;
X is 
xe2x80x83wherein
V1 and V2 are CH2, CO, CS, SO2 or CH(C1-C6 alkyl), with the proviso that both V1 and V2 cannot both be CO, CS or SO2;
Y1 and Y2 independently represent a bond or C1-C6 alkylene;
A1 is NR4 R5 wherein R4 and R5 are independently
hydrogen or a C1-C6 alkyl group which and optionally forms a heterocycloalkyl group with Y1;
acetyl or sulfonyl with the proviso that R4 and R5 cannot both be acetyl or sulfonyl; or
NR4R5 taken together form a C3-C6 heterocycloalkyl or a group of the formula: 
xe2x80x83wherein
e and f are independently 1, 2, or 3 and the sum of e and f is at least 3; and
G2 is
NR6 wherein R6 is hydrogen or C1-C6 alkyl, or
CH(C0-C6 alkylene)-G3xe2x80x94R7 wherein G3 is CONH, CONH(C1-C6 alkyl), NH, NH(C1-C6 alkyl) and R7 is hydrogen or C1-C6 alkyl; or
CONH2, CO[N(C1-C6 alkyl)R8] wherein R8 is hydrogen or C1-C6 alkyl;
A2 is hydrogen, C1-C6 alkyl, (C1-C6 alkylene)-G4xe2x80x94R9 wherein G4 is oxygen or sulfur and R9 is hydrogen, trifluoromethyl or C1-C6 alkyl; 
xe2x80x83wherein
heteroaryl is 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono- or disubstituted with halogen, trifluoromethyl, amino, C1-C6 alkyl, C1-C6 alkoxy, with the proviso that tetrazolyl can have at most one substituent;
Z1 is C1-C6 alkyl; and
V2, Y2 and A2 are as defined above; 
xe2x80x83wherein
Z2 is carbon or nitrogen;
where
when Z2 is CH, n is 0, 1, 2 or 3 and p is 1, 2, or 3, R10 is carboxamido, or (C1-C6 alkylene)-G5xe2x80x94R11 wherein G5 is NH, NH(C1-C6 alkyl) and R11 is hydrogen or C1-C6 alkyl;
when Z2 is carbon, n is 1 or 2 and p is 1 or 2, R10 is amino; or
when Z2 is nitrogen, n is 1 or 2 and p is 1 or 2, R10 is hydrogen; or
(iv) a nitrogen heterocycle of the formula: 
wherein the N-ring represents triazolyl, tetrazolyl, imidazolyl, or pyrazolyl, each of which is optionally substituted with amino, trifluoromethyl, carboxamido, or (C1-C6 alkylene)-G6xe2x80x94R12 wherein G6 is NH, NH(C1-C6 alkyl) and R12 is hydrogen or C1-C6 alkyl.
As noted above, the invention provides compounds of Formula I: 
wherein:
Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, carboxamido, C1-C6 alkyl, C1-C6 alkoxy, with the proviso that at least one of the positions ortho or para to the point of attachment of Ar to the tricyclic ring system is substituted;
R1 is hydrogen, halogen, trifluoromethyl, C1-C6 alkyl, or (C1-C6 alkyl)-G1xe2x80x94R2 where G1 is oxygen or sulfur and R2 is hydrogen or C1-C6 alkyl;
W is N or Cxe2x80x94R3 where R3 is hydrogen or C1-C6 alkyl;
m is 0, 1, or 2;
X is 
xe2x80x83wherein
V1 and V2 are CH2, CO, CS, SO2 or CH(C1-C6 alkyl), with the proviso that both V1 and V2 cannot both be CO, CS or SO2;
Y1 and Y2 independently represent a bond or C1-C6 alkylene;
A1 is NR4R5 wherein R4 and R5 are independently
hydrogen or a C1-C6 alkyl group which and optionally forms a heterocycloalkyl group with Y1;
acetyl or sulfonyl with the proviso that R4 and R5 cannot both be acetyl or sulfonyl; or
NR4R5 taken together form a C3-C6 heterocycloalkyl or a group of the formula: 
xe2x80x83wherein
e and f are independently 1, 2, or 3 and the sum of e and f is at least 3; and
G2 is
NR6 wherein R6 is hydrogen or C1-C6 alkyl, or
CH(C0-C6 alkylene)-G3 xe2x80x94R7 wherein G3 is CONH, CONH(C1-C6 alkyl), NH, NH(C1-C6 alkyl) and R7 is hydrogen or C1-C6 alkyl; or
CONH2, CO[N(C1-C6 alkyl)R8] wherein R8 is hydrogen or C1-C6 alkyl;
A2 is hydrogen, C1-C6 alkyl, (C1-C6 alkylene)-G4xe2x80x94R9 wherein G4 is oxygen or sulfur and R9 is hydrogen, trifluoromethyl or C1-C6 alkyl; 
xe2x80x83wherein
heteroaryl is 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono- or disubstituted with halogen, trifluoromethyl, amino, C1-C6 alkyl, C1-C6 alkoxy, with the proviso that tetrazolyl can have at most one substituent;
Z1 is C1-C6 alkyl; and
V2, Y2 and A2 are as defined above; 
xe2x80x83wherein
Z2 is carbon or nitrogen;
wherein
when Z2 is CH, n is 0, 1, 2 or 3 and p is 1, 2, or 3, R10 is carboxamido, or (C1-C6 alkylene)-G5xe2x80x94R11 wherein G5 is NH, NH(C1-C6 alkyl) and R11 is hydrogen or C1-C6 alkyl;
when Z2 is carbon, n is 1 or 2 and p is 1 or 2, R10 is amino; or
when Z2 is nitrogen, n is 1 or 2 and p is 1 or 2, R10 is hydrogen; or
(iv) a nitrogen heterocycle of the formula: 
wherein the N-ring represents triazolyl, tetrazolyl, imidazolyl, or pyrazolyl, each of which is optionally substituted with amino, trifluoromethyl, carboxamido, or (C1-C6 alkylene)-G6xe2x80x94R12 wherein G6 is NH, NH(C1-C6 alkyl) and R12 is hydrogen or C1-C6 alkyl.
Preferred compounds of Formula I are those where V1 and V2 represent methylene; Y1 is a bond; A1 represents pyrrolidinyl, morpholinyl; piperazinyl, or mono- or di-C1-C6 alkyl; Y2 represents a bond or methylene; and A2 represents C1-C6 alkyl or C1-C6 alkoxymethyl.
Other preferred compounds of Formula I are those where each Ra independently represents C1-C6 alkyl; and A2 is C1-C6 cycloalkyl. In other preferred compounds of I, A2 is (C3-C5) cycloalkyl (C1-C4 )alkyl.
Still other preferred compounds of I include are those where
A1 is
NR4R5 where R4 and R5 are independently hydrogen, C1-C6 alkyl; or
NR4R5 forms a 5 or 6-membered nitrogen heterocycle optionally containing an oxygen or second nitrogen atom;
Y1 is C1-C6 alkylene;
Y2 is a bond or C1-C6 alkylene;
V1 is methylene; and V2 is methylene.
More preferably, A2 is (C3-C5)cycloalkyl. Still more preferably, R4 and R5 are independently C1-C6 alkyl. Other particularly preferred compounds of Formula I are those where each Ra is methyl; Y2 is a bond; and R4 and R5 are the same and represent C1-C3 alkyl.
In yet other preferred compounds of Formula I, m is 1 or 2, more preferably 1. In still other preferred compounds of I, m is 1 and R1 is C1-C3 alkyl, more preferably methyl.
Preferred compounds of the invention have Formula II: 
wherein:
each Ra independently represents C1-C6 alkyl;
R1 is hydrogen, halogen, trifluoromethyl, C1-C6 alkyl, or (C1-C6 alkyl)-G1xe2x80x94R2 where G1 is oxygen or sulfur and R2 is hydrogen or C1-C6 alkyl;
W is N or Cxe2x80x94R3 where R3 is hydrogen or C1-C6 alkyl;
m is 0, 1, or 2;
X is 
xe2x80x83wherein
V1 and V2 are CH2, CO, CS, SO2 or CH(C1-C6 alkyl), with the proviso that both V1 and V2 cannot both be CO, CS or SO2; 
Y1 and Y2 independently represent a bond or C1-C6 alkylene;
A1 is NR4R5 wherein R4 and R5 are independently
hydrogen or a C1-C6 alkyl group which and optionally forms a heterocycloalkyl group with Y1 ;
acetyl or sulfonyl with the proviso that R4 and R5 cannot both be acetyl or sulfonyl; or
NR4R5 taken together form a C3-C6 heterocycloalkyl or a group of the formula: 
xe2x80x83wherein
e and f are independently 1, 2, or 3 and the sum of e and f is at least 3; and
G2 is
NR6 wherein R6 is hydrogen or C1-C6 alkyl, or
CH(C0-C6 alkylene)-G3xe2x80x94R7 wherein G3 is CONH, CONH(C1-C6 alkyl), NH, NH(C1-C6 alkyl) and R7 is hydrogen or C1-C6 alkyl; or
CONH2, CO[N(C1-C6 alkyl)R8] wherein R8 is hydrogen or C1-C6 alkyl;
A2 is hydrogen, C1-C6 alkyl, (C1-C6 alkylene)-G4xe2x80x94R9 wherein G4 is oxygen or sulfur and R9 is hydrogen, trifluoromethyl or C1-C6 alkyl; 
xe2x80x83wherein
heteroaryl is 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono- or disubstituted with halogen, trifluoromethyl, amino, C1-C6 alkyl, C1-C6 alkoxy, with the proviso that tetrazolyl can have at most one substituent;
Z1 is C1-C6 alkyl; and
V2, Y2 and A2 are as defined above; 
xe2x80x83wherein
Z2 is carbon or nitrogen;
wherein
when Z2 is CH, n is 0, 1, 2 or 3 and p is 1, 2, or 3, R10 is carboxamido, or (C1-C6 alkylene)-G5xe2x80x94R11 wherein G5 is NH, NH(C1-C6 alkyl) and R11 is hydrogen or C1-C6 alkyl;
when Z2 is carbon, n is 1 or 2 and p is 1 or 2, R10 is amino; or
when Z2 is nitrogen, n is 1 or 2 and p is 1 or 2, R10 is hydrogen; or
(iv) a nitrogen heterocycle of the formula: 
wherein the N-ring represents triazolyl, tetrazolyl, imidazolyl, or pyrazolyl, each of which is optionally substituted with amino, trifluoromethyl, carboxamido, or (C1-C6 alkylene)-G6 xe2x80x94R12 wherein G6 is NH, NH(C1-C6 alkyl) and R12 is hydrogen or C1-C6 alkyl.
Preferred compounds of Formula II are those where V1 and V2 represent methylene; Y1 is a bond; A1 represents pyrrolidinyl, morpholinyl; piperazinyl, or mono- or di-C1-C6 alkyl; Y2 represents a bond or methylene; and A2 represents C1-C6 alkyl or C1-C6 alkoxymethyl.
Other preferred compounds of Formula II are those where
each Ra independently represents C1-C6 alkyl;
A2 is (C3-C5)cycloalkyl(C1-C4)alkyl or (C3-C5)cycloalkyl;
A1 is
NR4R5 where R4 and R5 are independently hydrogen, C1-C6 alkyl; or
NR4R5 forms a 5 or 6-membered nitrogen heterocycle optionally containing an oxygen or second nitrogen atom;
Y1 is C1-C6 alkylene;
Y2 is a bond or C1-C6 alkylene;
V1 is methylene; and V2 is methylene.
More preferably, A2 is cyclopropyl(C1-C3)alkyl or (C3-C5)cycloalkyl; and R4 and R5 are independently C1-C6 alkyl. Particularly preferred compounds of Formula II include those where A2 is (C3-C5) cycloalkyl; Y2 is a bond; and R4 and R5 are the same and represent C1-C3 alkyl. Other particularly preferred compounds of Formula II are those where each Ra is methyl; A2 is cyclopropyl; Y2 is a bond; and R4 and R5 are the same and represent C1-C3 alkyl.
In preferred compounds of Formula II, m is 1 or 2, more preferably 1. In other preferred compounds of II, m is 1 and R1 is C1-C3 alkyl, more preferably methyl.
Other preferred compounds of the invention have Formula III: 
wherein:
each Ra independently represents C1-C6 alkyl;
R1 is hydrogen, halogen, trifluoromethyl, C1-C6 alkyl, or (C1-C6 alkyl)-G1xe2x80x94R2 where G1 is oxygen or sulfur and R2 is hydrogen or C1-C6 alkyl;
W is N or Cxe2x80x94R3 where R3 is hydrogen or C1-C6 alkyl;
m is 0, 1, or 2;
X is 
xe2x80x83wherein
V1 and V2 are CH2, CO, CS, SO2 or CH(C1-C6 alkyl), with the proviso that both V1 and V2 cannot both be CO, CS or SO2;
Y1 and Y2 independently represent a bond or C1-C6 alkylene;
A1 is NR4R5 wherein R4 and R5 are independently
hydrogen or a C1-C6 alkyl group which and optionally forms a heterocycloalkyl group with Y1;
acetyl or sulfonyl with the proviso that R4 and R5 cannot both be acetyl or sulfonyl; or
NR4R5 taken together form a C3-C6 heterocycloalkyl or a group of the formula: 
xe2x80x83wherein
e and f are independently 1, 2, or 3 and the sum of e and f is at least 3; and
G2 is
NR6 wherein R6 is hydrogen or C1-C6 alkyl, or
CH(C0-C6 alkylene)-G3xe2x80x94R7 wherein G3 is CONH, CONH(C1-C6 alkyl), NH, NH(C1-C6 alkyl) and R7 is hydrogen or C1-C6 alkyl; or
CONH2, CO[N(C1-C6 alkyl)R8] wherein R8 is hydrogen or C1-C6 alkyl;
A2 is hydrogen, C1-C6 alkyl, (C1-C6 alkylene)-G4xe2x80x94R9 wherein G4 is oxygen or sulfur and R9 is hydrogen, trifluoromethyl or C1-C6 alkyl; 
xe2x80x83wherein
heteroaryl is 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono- or disubstituted with halogen, trifluoromethyl, amino, C1-C6 alkyl, C1-C6 alkoxy, with the proviso that tetrazolyl can have at most one substituent;
Z1 is C1-C6 alkyl; and
V2, Y2 and A2 are as defined above; 
xe2x80x83wherein
Z2 is carbon or nitrogen;
wherein
when Z2 is CH, n is 0, 1, 2 or 3 and p is 1, 2, or 3, R10 is carboxamido, or (C1-C6 alkylene)-G5xe2x80x94R11 wherein G5 is NH, NH(C1-C6 alkyl) and R11 is hydrogen or C1-C6 alkyl;
when Z2 is carbon, n is 1 or 2 and p is 1 or 2, R10 is amino; or
when Z2 is nitrogen, n is 1 or 2 and p is 1 or 2, R10 is hydrogen; or
(iv) a nitrogen heterocycle of the formula: 
wherein the N-ring represents triazolyl, tetrazolyl, imidazolyl, or pyrazolyl, each of which is optionally substituted with amino, trifluoromethyl, carboxamido, or (C1-C6 alkylene)-G6xe2x80x94R12 wherein G6 is NH, NH(C1-C6 alkyl) and R12 is hydrogen or C1-C6 alkyl.
Preferred compounds of Formula III are those where V1 and V2 represent methylene; Y1 is a bond; A1 represents pyrrolidinyl, morpholinyl; piperazinyl, or mono- or di-C1-C6 alkyl; Y2 represents a bond or methylene; and A2 represents C1-C6 alkyl or C1-C6 alkoxymethyl.
Other preferred compounds of Formula III include those where each Ra is independently halogen, trifluoromethyl, hydroxy, amino, C1-C6 alkyl, or C1-C6 alkoxy. Specific preferred compounds of III are those where at least one Ra is C1-C6 alkyl and the other Ra groups are independently C1-C6 alkyl, halogen, C1-C6 alkoxy or trifluoromethyl.
Other preferred compounds of Formula III are those where each Ra independently represents C1-C6 alkyl;
A2 is (C3-C5)cycloalkyl(C1-C4)alkyl or (C3-C5)cycloalkyl;
A1 is
NR4R5 where R4 and R5 are independently hydrogen, C1-C6 alkyl; or
NR4R5 forms a 5 or 6-membered nitrogen heterocycle optionally containing an oxygen or second nitrogen atom;
Y1 is C1-C6 alkylene;
Y2 is a bond or C1-C6 alkylene;
V1 is methylene; and V2 is methylene.
More preferably, A2 is cyclopropyl(C1-C3)alkyl or (C3-C5)cycloalkyl; and R4 and R5 are independently C1-C6 alkyl. Particularly preferred compounds of Formula III include those where A2 is (C3-C5)cycloalkyl; Y2 is a bond; and R4 and R5 are the same and represent C1-C3 alkyl. Other particularly preferred compounds of Formula III include those where at least one Ra is methyl; A2 is (C3-C5) cycloalkyl; Y2 is a bond; and R4 and R5 are the same and represent C1-C3 alkyl. Highly preferred compounds of Formula III are those where each Ra is methyl; A2 is cyclopropyl; Y2 is a bond; and R4 and R5 are the same and represent C1-C3alkyl.
In preferred compounds of Formula III, m is 1 or 2, more preferably 1. In other preferred compounds of III, m is 1 and R1 is C1-C3 alkyl, more preferably methyl.
In certain situations, the compounds of Formula I may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates or optically active forms. In these situations, the single enantiomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column.
Representative compounds of the present invention, which are encompassed by Formula I, include, but are not limited to the compounds in Table I and their pharmaceutically acceptable acid addition salts. In addition, if the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
Non-toxic pharmaceutical salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOCxe2x80x94(CH2)n-ACOOH where n is 0-4, and the like. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.
The present invention also encompasses the acylated prodrugs of the compounds of Formula I. Those skilled in the art will recognize various synthetic methodologies which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I.
By xe2x80x9calkylxe2x80x9d or xe2x80x9clower alkylxe2x80x9d in the present invention is meant C1-C6 alkyl, i.e., straight or branched chain alkyl groups having 1-6 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl and straight or branched chain alkyl groups of 1-5 carbon atoms carrying a cyclopropyl, cyclobutyl, or cyclopenlyl group. Preferred C1-C6 alkyl groups are methyl, ethyl, propyl, butyl, cyclopropyl or cyclopropylmethyl.
By xe2x80x9cC0-C6 alkylenexe2x80x9d is meant a direct bond or a C1-C6 alkylene group.
By xe2x80x9calkoxyxe2x80x9d or xe2x80x9clower alkoxyxe2x80x9d in the present invention is meant C1-C6 alkoxy, i.e., straight or branched chain alkoxy groups having 1-6 carbon atoms, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.
CONH represents an amide functional group, i.e., 
The term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocycloalkylxe2x80x9d means a monocyclic or bicyclic hydrocarbon group which in which one or more of the ring carbon atoms has been replaced with a heteroatom, e.g., oxygen, sulfur or nitrogen. Such groups preferably have 4 to 10 carbon atoms and 1 to 4 heteroatoms.
By the term xe2x80x9chalogenxe2x80x9d in the present invention is meant fluorine, bromine, chlorine, and iodine.
Table 1 shows representative aminoalkyl substituted 5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole and 5,6,7,8-tetrahydro-9H-pyrimidino[4,5-b]indole derivatives of the present invention. The number under each compound is its compound number.
The interaction of aminoalkyl substituted 5,6,7,8-tetrahydro-9H-pyridino[2,3-b]indole and 5,6,7,8-tetrahydro-9H-pyrimidino[4,5-b]indole derivatives of the invention with CRF receptors is shown in the examples. This interaction results in the pharmacological activities of these compounds as illustrated in relevant animal models.
The compounds of general Formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition, there is provided a pharmaceutical formulation comprising a compound of general Formula I and a pharmaceutically acceptable carrier. One or more compounds of general Formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing compounds of general Formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of general Formula I may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
Compounds of general Formula I may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
Representative preparations of compounds of the present invention are shown in Schemes I, II, III and IV. Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the present invention. 
wherein Ar, R1 and R3 are as defined above for Formula I; and R14, R15 and R16 are encompassed by the definition of X in Formula I; 
wherein Ar, R1 and R3 are as defined above for Formula I; and R14, R15 and R16 are encompassed by the definition of X in Formula I; 
wherein Ar, R1 and R3 are as defined above for Formula I; and R15 and R16 are encompassed by the definition of X in Formula I; 
wherein Ar and R1 are as defined with reference to Formula I; R15, R16 and R17 are as defined above in Formula I with respect to the definition of X;
The preparation of the compounds of the present invention is illustrated further by the following examples, which are not to be construed as limiting the invention in scope or spirit to the specific procedures and compounds described in them.
The disclosures of all articles and references mentioned in in this application, including patents, are incorporated herein by reference.
Commercial reagents were used without further purification. THF refers to tetrahydrofuran. LDA refers to lithium diisopropylamide. Room or ambient temperature refers to 20 to 25xc2x0 C. Concentration implies the use of a rotary evaporator. TLC refers to thin layer chromatography. Mass spectral data were obtained either by CI or APCI methods.